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Real-World Evidence (RWE), which has historically been used to support post-approval safety studies, has recently gained acceptance for new drug applications as supportive evidence or as new clinical evidence for medicinal products with orphan designation and/or in disease areas with high unmet need. Here, we present a case study for the use of RWE in the approval of abaloparatide in the European Union (EU) under the tradename Eladynos. In addition to data from the pivotal Phase 3 study, the marketing authorization application (MAA) included clinical data from additional interventional and observational studies, as well as post-marketing data obtained from the United States (US) market since approval of abaloparatide by the Food and Drug Administration (FDA) in 2017. The new interventional studies were not designed to assess fracture efficacy and cardiovascular safety which were topics of concern raised by the Committee for Medicinal Products for Human Use (CHMP) during their review of the initial MAA submitted in 2015. However, these studies taken together with the RWE formed the basis for a new MAA. Prior to the planned resubmission in the EU, national Scientific Advice (SA) was sought on the proposed clinical program, specifically on the relevance of Real-World Data (RWD) derived from an observational study to support and complement the efficacy and safety data already available from prospective randomized clinical trials. This case study demonstrates successful use of RWE to address a previously identified gap raised by the CHMP during the review of an earlier MAA, which led to the approval of Eladynos for the treatment of osteoporosis in the EU.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.amjmed.2009.01.033 Byline: Elizabeth Barrett-Connor (a), David A. Cox (b), Jingli Song (b), Bruce Mitlak (b), Lori Mosca (c), Deborah Grady (d) Keywords: Framingham; Raloxifene; SERM; Stroke Abstract: Raloxifene reduces vertebral fracture and invasive breast cancer risks, but increases fatal strokes in postmenopausal women at increased coronary risk. We assessed whether this risk is concentrated in postmenopausal women already at high stroke risk. Author Affiliation: (a) Departments of Family and Preventive Medicine, University of California, San Diego, La Jolla, Calif (b) Lilly Research Laboratories, Indianapolis, Ind (c) Preventive Cardiology, Columbia University Medical Center, New York, NY (d) University of California, San Francisco and the San Francisco VA Medical Center, Calif Article Note: (footnote) Funding: Studies funded by Lilly Research Laboratories., Conflict of Interest: Elizabeth Barrett-Connor and Deborah Grady were paid external investigators for the Raloxifene MORE and RUTH studies by Lilly Research Laboratories. Lori Mosca was a paid external investigator for the Raloxifene RUTH study by Lilly Research Laboratories. David A. Cox, Jingli Song, and Bruce Mitlak are employees of Lilly Research Laboratories and have financial interest in the company., Authorship: All authors had access to the data and a role in writing the manuscript.

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The validation of bone mineral density (BMD) as a surrogate outcome for fracture would allow the size of future randomised controlled osteoporosis registration trials to be reduced. We aimed to determine the association between treatment-related changes in BMD, assessed by dual-energy x-ray absorptiometry, and fracture outcomes, including the proportion of treatment effect explained by BMD changes.

Background: In postmenopausal women, raloxifene hydrochloride has favorable effects on bone and lipid metabolism and does not stimulate reproductive tissues. The studies reported herein evaluated the long-term (3-year) effects of raloxifene treatment on bone mineral density (BMD), serum lipid levels, and drug tolerability in healthy postmenopausal women. Methods: A total of 1145 healthy European and North American postmenopausal women aged 45 through 60 years were enrolled in 2 parallel, double-blind, randomized, placebo-controlled trials of identical design and randomly assigned to receive raloxifene hydrochloride, 30, 60, or 150 mg, or placebo daily; all groups received 400 to 600 mg of elemental calcium. Assessments included measurements for BMD by dual-energy x-ray absorptiometry, markers of bone turnover, and serum lipid levels. Results: Lumbar spine BMD changed from baseline to 36 months as follows: placebo (mean percentage change [+ or -] SE), -1.32% [+ or -] 0.22%; raloxifene, 30 mg, 0.71% [+ or -] 0.23%; raloxifene, 60 mg, 1.28% [+ or -] 0.23%; and raloxifene, 150 mg, 1.20% [+ or -] 0.24%. Comparable BMD changes were observed in the hip and total body. Biochemical markers of bone turnover were suppressed by raloxifene to normal premenopausal ranges through 3 years. Serum low-density lipoprotein cholesterol was reduced 7% to 12% below baseline through 3 years. Study withdrawals due to any reason (37%) and withdrawals due to adverse events (14%) were not different among groups. The only significant adverse effect of therapy was hot flashes (25% in the 60-mg raloxifene group vs 18% in the placebo group); hot flashes were typically reported as mild and were not associated with study withdrawal (1.7% for 60-mg raloxifene vs 2.4% for placebo). Conclusions: Raloxifene preserves BMD at important skeletal sites, lowers serum low-density lipoprotein cholesterol levels, and has a tolerability profile comparable to placebo. These results indicate a favorable benefit-risk profile of raloxifene for long-term use in healthy postmenopausal women. Arch Intern Med. 2000;160:3444-3450

In ACTIVExtend, reductions in fracture risk and increases in BMD achieved with 18 months of abaloparatide for postmenopausal osteoporosis were sustained through 24 months of subsequent alendronate.

Sarcopenia is an age-related muscle condition which is frequently a precursor of frailty, mobility disability and premature death. It has a high prevalence in older populations and presents a considerable social and economic burden. Potential treatments are under development but, as yet, no guidelines support regulatory studies for new drugs to manage sarcopenia. The objective of this position paper is therefore to suggest a set of potential endpoints and target population definitions to stimulate debate and progress within the medico-scientific and regulatory communities. A multidisciplinary expert working group was hosted by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, which reviewed and discussed the recent literature from a perspective of clinical experience and guideline development. Relevant parallels were drawn from the development of definition of osteoporosis as a disease and clinical assessment of pharmaceutical treatments for that indication. A case-finding decision tree is briefly reviewed with a discussion of recent prevalence estimations of different relevant threshold values. The selection criteria for patients in regulatory studies are discussed according to the aims of the investigation (sarcopenia prevention or treatment) and the stage of project development. The possible endpoints of such studies are reviewed and a plea is made for the establishment of a core outcome set to be used in all clinical trials of sarcopenia. The current lack of guidelines for the assessment of new therapeutic treatments for sarcopenia could potentially hinder the delivery of effective medicines to patients at risk.

Tamoxifen and raloxifene reduce the risk of breast cancer in women at elevated risk of disease, but the duration of the effect is unknown. We assessed the effectiveness of selective oestrogen receptor modulators (SERMs) on breast cancer incidence.

Several studies have concluded that diabetes mellitus and heart disease carry similar risk for future cardiovascular disease (CVD). Most of these studies were too small to quantify independent risks specific to women. The purpose of this study was to determine whether diabetes mellitus is a coronary heart disease (CHD) risk equivalent for prediction of future CHD and CVD events in women.

A follow‐up in 1262 women was conducted after the discontinuation of teriparatide. The hazard ratio for combined teriparatide group (20 and 40 μg) for the 50‐month period after baseline was 0.57 (p= 0.002), suggesting a sustained effect in reducing the risk of nonvertebral fragility fracture.

Histomorphometry and μCT of 51 paired iliac crest biopsy specimens from women treated with teriparatide revealed significant increases in cancellous bone volume, cancellous bone connectivity density, cancellous bone plate‐like structure, and cortical thickness, and a reduction in marrow star volume.Introduction:We studied the ability of teriparatide (rDNA origin) injection [rhPTH(1–34), TPTD] to improve both cancellous and cortical bone in a subset of women enrolled in the Fracture Prevention Trial of postmenopausal women with osteoporosis after a mean treatment time of 19 months. This is the first report of a biopsy study after treatment with teriparatide having a sufficient number of paired biopsy samples to provide quantitative structural data.Methods:Fifty‐one paired iliac crest bone biopsy specimens (placebo [n= 19], 20 μg teriparatide [n= 18], and 40 μg teriparatide [n= 14]) were analyzed using both two‐dimensional (2D) histomorphometry and three‐dimensional (3D) microcomputed tomography (μCT). Data for both teriparatide treatment groups were pooled for analysis.Results and Conclusions:By 2D histomorphometric analyses, teriparatide significantly increased cancellous bone volume (median percent change: teriparatide, 14%; placebo, −24%; p= 0.001) and reduced marrow star volume (teriparatide, −16%; placebo, 112%; p= 0.004). Teriparatide administration was not associated with osteomalacia or woven bone, and there were no significant changes in mineral appositional rate or wall thickness. By 3D cancellous and cortical bone structural analyses, teriparatide significantly decreased the cancellous structure model index (teriparatide, −12%; placebo, 7%; p= 0.025), increased cancellous connectivity density (teriparatide, 19%; placebo, −14%; p= 0.034), and increased cortical thickness (teriparatide, 22%; placebo, 3%; p= 0.012). These data show that teriparatide treatment of postmenopausal women with osteoporosis significantly increased cancellous bone volume and connectivity, improved trabecular morphology with a shift toward a more plate‐like structure, and increased cortical bone thickness. These changes in cancellous and cortical bone morphology should improve biomechanical competence and are consistent with the substantially reduced incidences of vertebral and nonvertebral fractures during administration of teriparatide.

In a recent study of women with postmenopausal osteoporosis, treatment with teriparatide for a median of 19 months increased bone mineral density and decreased the risk of vertebral and nonvertebral fractures. Using the same cohort, the current study evaluated the relationship between these therapeutic effects and the patient's baseline age, vertebral bone mineral density, and prevalent vertebral fractures. In women over 65 years of age, treatment resulted in a greater increase in vertebral bone mineral density than in younger women (treatment‐by‐age interaction, p= 0.037), but baseline age had no effect on the relative risk reduction for vertebral fractures (treatment‐by‐age interaction, p= 0.558). In women receiving placebo (with calcium and vitamin D), there was an inverse relationship between baseline vertebral bone mineral density and vertebral fracture risk. When compared across bone mineral density tertiles, the effects of teriparatide on the relative risk for developing new vertebral fractures and increase in vertebral bone mineral density did not differ significantly (p= 0.817 and p= 0.615, respectively). Teriparatide treatment significantly decreased vertebral fracture risk in patients with a vertebral bone mineral density T score of less than −3.3 or a score between −2.1 and −3.3 (p< 0.001 and p= 0.027, respectively) and showed a trend toward reduced fracture risk in the group with a T score greater than −2.1 (p= 0.115). Placebo‐treated women with two or more prevalent vertebral fractures had a significantly greater risk of developing new vertebral fractures than women with zero or one prevalent vertebral fracture (p< 0.001). When compared within prevalent vertebral fracture subgroups, the effects of teriparatide on the relative risk for developing new vertebral fractures were similar. The results of this study indicate that teriparatide offers clinical benefit to patients across a broad range of age and disease severity.

Although low absolute values of bone mineral density (BMD) predict increased fracture risk in osteoporosis, it is not certain how well increases in BMD with antiresorptive therapy predict observed reductions in fracture risk. This work examines the relationships between changes in BMD after 1 year or 3 years of raloxifene or placebo therapy and the risk for new vertebral fractures at 3 years. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis were randomized to placebo or raloxifene 60 mg/day or 120 mg/day. Relationships between baseline BMD and changes in BMD from baseline with the risk of new vertebral fractures were analyzed in this cohort using logistic regression models with the raloxifene doses pooled. As has been observed in other populations, women with the lowest baseline lumbar spine or femoral neck BMD in the MORE cohort had the greatest risk for vertebral fractures. Furthermore, for any percentage change, either increase or decrease in femoral neck or lumbar spine BMD at 1 year or 3 years, raloxifene‐treated patients had a statistically significantly lower vertebral fracture risk compared with placebo‐treated patients. The decrease in fracture risk with raloxifene was similar across the range of percentage change in femoral neck BMD observed at 3 years; patients receiving raloxifene had a 36% lower risk of vertebral fracture compared with those receiving placebo. At any percentage change in femoral neck and lumbar spine BMD observed at 1 year, raloxifene treatment decreased the risks of new vertebral fractures at 3 years by 38% and 41%, respectively. The logistic regression model showed that the percentage changes in BMD with raloxifene treatment accounted for 4% of the observed vertebral fracture risk reduction, and the other 96% of the risk reduction remains unexplained. The present data show that the measured BMD changes observed with raloxifene therapy are poor predictors of vertebral fracture risk reduction with raloxifene therapy.

To determine the endometrial effects of raloxifene 60 mgday in postmenopausal women as assessed by vaginal bleeding and endometrial thickness.

We examined the effect of intermittent administration of bovine parathyroid hormone (1–34) (bPTH) on spinal bone mineral content (BMC) and bone mineral density (BMD), serum 1,25‐dihydroxyvitamin D concentrations, and serum markers of osteoblast function in senile male and female rats (23 and 24 months of age, respectively). Sexually mature young (3 month) male rats were similarly treated for comparison. bPTH administration increased serum osteocalcin concentrations without changing serum inorganic phosphate or calcium concentrations in either group of old animals. In young animals, PTH administration increased the serum calcium and inorganic phosphate concentrations significantly (p< 0.05), although values remained within the normal range. In the vehicle‐treated male rats, serum 1,25‐dihydroxyvitamin D concentrations were lower in the senile than in the young animals (18 ± 5 versus 47 ± 6 pg/ml, p< 0.05). PTH administration resulted in significantly increased serum 1,25‐dihydroxyvitamin D concentrations in the senile and young male animals (both, p< 0.05) and the final mean serum 1,25‐dihydroxy vitamin D concentrations were not statistically different (68 ± 9 versus 85 ± 6 pg/ml respectively; p= NS). Serum 1,25‐dihydroxyvitamin D concentrations were significantly (p< 0.05) higher in the PTH‐treated senile female rats than the sex‐matched, vehicle‐treated controls. The pretreatment spinal BMC and BMD as assessed by dual‐energy x‐ray absorptiometry (DEXA) were significantly higher in the senile male animals than in the young animals. Spinal BMC and BMD decreased in the vehicle‐treated senile male rats (p< 0.05) over the 3 weeks of the study despite a gain in weight. bPTH administration prevented this fall in spinal BMC and increased spinal BMD (p< 0.05). Spinal BMC and BMD increased significantly (p< 0.05) in the young vehicle‐treated rats, and PTH administration caused a further significant increase in both parameters of bone mass. Spinal BMD was significantly (p< 0.05) higher in the PTH‐treated senile female rats than in vehicle‐treated controls. These findings demonstrate that intermittent PTH administration increases serum 1,25‐dihydroxyvitamin D concentrations of senile animals to the levels of PTH‐treated, young, sexually mature animals. In addition, PTH administration arrests bone loss and increases spinal BMD of senile rats.

Of 118 consecutive white patients referred for asymptomatic primary hyperparathyroidism, the diagnosis was clinically confirmed in 100, of whom 85 adults had a serum calcium less than 3.0 mM (12 mg/dl) and no skeletal, rheumatic, or significant neuropsychiatric symptoms, azotemia, or other significant illnesses. Among these 85, 68 had both asymptomatic and medically uncomplicated hyperparathyroidism, whereas 17 had historical, radiographic, or ultrasonic evidence of renal stone disease. The 20% with past or present renal calculi concentrated their urine significantly better than the 68 others (p= 0.05), but these two groups were otherwise not distinguished by the tests we performed, so all 85 patients were analyzed together. Systolic and diastolic blood pressures were normal, but premature osteopenia and/or impaired renal function were present in 29–36% of the patients. Micrometer measurements of metacarpal radiographs and 125I photon absorptiometry at the shaft of the radius revealed cortical osteopenia. Osteopenia was equally significant in the distal radius (cortical plus trabecular bone). These quantitative measurements were superior to routine bone radiography, and ROC analysis showed that 125I absorptiometry at either site was superior (p< 0.01) to metacarpal cortex measurements for detecting premature osteopenia, which was present in more than a third of these patients. Creatinine clearances (24 h) and maximum urine concentrating capacity (overnight dehydration plus the synthetic vasopressin analog DDAVP) were each significantly reduced, despite all patients' normal BUN and serum creatinine levels. Sequential performance of a 24 h creatinine clearance and a urine concentration test revealed abnormalities in the renal function of 27 of 74 patients (36%), with a specificity of 95% and a higher sensitivity than either test alone (27–29%). Testing the kidneys' ability to acidify the urine to pH 5.3 or less identified only 1 additional abnormal patient. Silent complications of primary hyperparathyroidism are thus common in “asymptomatic” patients with mild hypercalcemia. Their presence was only weakly correlated with urinary calcium excretion (measured on a low‐calcium diet) and serum alkaline phosphatase. From these data, it is not possible to predict whether these complications progress in the absence of treatment or diminish with successful treatment of the primary hyperparathyroidism.

Platelet‐derived growth factor (PDGF), an osteoblast mitogen, has been demonstrated to accelerate fracture healing and periodontal bone repair when applied locally in vivo. To explore whether PDGF could stimulate bone formation in intact bone, we administered it systemically to rats rendered acutely estrogen‐deficient. Because PDGF may stimulate bone resorption in vitro, PDGF was administered with and without an antiresorptive agent (alendronate). All treatments were given by intravenous injection 3 times a week for 6 weeks. Spinal bone mineral density (BMD) decreased by 5% in the vehicle‐treated ovariectomized (OVX) rats by the end of the study as determined by DXA. Treatment with PDGF prevented this bone loss and significantly (p< 0.05) increased the bone density in the spine (9%) and whole skeleton (5.8%). Combined treatment with PDGF and alendronate resulted in a greater increase at the spine (18%) and whole skeleton (12.8%) than either agent alone. Histomor‐phometric analysis demonstrated that treatment with PDGF increased the osteoblast number and osteoblast perimeter without consistent changes in osteoclast estimates. Biomechanical testing demonstrated that PDGF administration increased the vertebral body compressive strength and femoral shaft torsional stiffness and resulted in a trend for enhanced femoral head shearing strength. Coadministration of alendronate further increased these indices of bone strength. PDGF administration also caused premature closure of the growth plate, decreased body fat, and resulted in extraskeletal collagen deposition. We therefore demonstrate, for the first time, that systemic administration of PDGF can increase bone density and strength throughout the skeleton.

We evaluated the precision and accuracy of dual‐energy x‐ray bone densitometry (DXA) in 38 male and female rats aged 1–10 months. The coefficients of variation (CV) estimated from same‐day paired measurements of bone mineral content (BMC) were 1.26% at the lumbar spine and 0.69% at the whole skeleton, and the corresponding CV for BMC corrected for projected bone area (i.e., bone mineral density, BMD) were 0.57 and 0.66%. BMC, measured in vivo, correlated closely with the subsequently determined ash weights (spine r2= 0.94, whole‐skeleton r2= 0.97). The long‐term CV for BMC measurements, assessed by measuring a frozen animal daily for 4 weeks, were 1.28% for the spine and 1.03% for the whole skeleton; for BMD the corresponding CV were 0.88 and 1.15%. To examine the utility of serial DXA measurements we followed female rats subjected to ovariectomy (OVX) or sham operation at 10 months of age and male rats given daily subcutaneous injections of hPTH‐(1–34) or vehicle starting at 10 months of age every 3 weeks for 15 weeks. In the OVX rats a progressive decrease in spine BMC was observed that was most rapid during the first 6 weeks. By 15 weeks the mean spine BMC decreased by 17% in the OVX rats (p< 0.007 versus sham operation). OVX did not affect the accuracy of DXA measurements as assessed by comparison with the ash weight at the end of the 15 week study. PTH treatment increased spine BMC by a mean of 32% and increased whole‐skeleton BMC by a mean of 19% within 15 weeks. The long‐term in vivo variation was estimated by fitting a model for BMC and BMD in the vehicle‐treated male rats and sham‐operated female rats, assuming a linear rate of change over the 15 weeks and a different slope and intercept for each animal; the residual root mean squared error was taken as an estimate of variability. Defined in this manner, the long‐term variation for BMC measurements in vivo is 5% for the spine and 3% for the whole skeleton; for BMD the corresponding figures are 3 and 2%. This variability is significantly greater than that attributable to instrumental variation and/or same‐day repositioning and must be considered when designing experiments requiring serial measurements.XS

Although daily injections of parathyroid hormone (PTH) can rapidly reverse estrogen‐deficiency bone loss in rats, PTH treatment of osteoporotic humans has to date produced more modest increases in bone mass. To explore the reasons for this important difference, we evaluated the dose‐ and time‐dependence of human PTH 1–84 treatment effects on bone mass and biochemical markers of bone metabolism in rats with estrogen‐deficiency bone loss. The highest doses of PTH increased spinal, femoral, and total skeletal mass to supra‐normal levels and stimulated cortical endosteal bone formation. Spine and whole skeleton mass and density increased rapidly at first, but then increased more slowly; the rate of change decreased significantly (p< 0.01) during continued treatment with the highest doses of PTH. The effects of PTH treatment on biochemical markers also were both dose‐dependent and time‐dependent. Serum osteocalcin, a marker of osteoblast function, increased with the highest doses of PTH (p< 0.001), but reached an early plateau and later returned toward baseline. Urinary excretion of pyridinolines, a marker of osteoclast function, increased in a time‐dependent fashion throughout treatment (p< 0.001). Serum 1,25(OH)2vitamin D levels increased in a dose‐related fashion, but then decreased toward control levels despite continued treatment. We demonstrate that both osteoblast and osteoclast function are increased during daily PTH therapy in the rat. The pattern of response depends on both the dose of PTH and the duration of therapy. These dose‐ and time‐related effects should be taken into account when designing experimental PTH treatments for osteoporosis, and they deserve intensive study.

We Evaluated Spinal And Femoral Bone Mass And Density Utilizing Dual‐Energy X‐Ray Absorptiometry (Dexa) In Rats In Which Severe Hyperparathyroidism Was Produced By The Expression Of The Gene For Human Pth‐(1–84) (Hpth). This Gene Was Incorporated Into A Retroviral Vector That Was Transfected Into Fibroblasts Which Were Subsequently Injected Into Their Peritoneal Cavities. Further, We Examined The Effect Of The Administration Of Pamidronate On Bone Mass And Density In The Presence Of Extremely High Concentrations Of Hpth. Three Groups Of Rats Were Studied. Groups 1 And 2 Receive The Hpth‐Secreting Fibroblasts; Group 2 Subsequently Received Pamidronate (2.5 Mg/Kg Iv) 18 And 27 Days After Receiving The Fibroblasts. These Animals Developed Levels Of Hpth > 1.0 μg/Liter And Became Hypercalcemia Within 20 Days. These Animals Became Lethargic And Were Significantly Lower In Weight Than Age‐Matched Controls (Group 3, P< 0.05). After Accounting For The Animal Weight There Was A Further Significant Decrease In Bone Mineral Content And Density (Bmc And Bmd) On Day 29 Attributable To Hpth‐Mediated Bone Loss. Treatment With Pamidronate Resulted In A Higher Bmc Of The Lumbar Spine Than In The Untreated Animals, With Elevated Concentrations Of Hpth. The Bmd Was Significantly Higher At Both The Lumbar Spine And Femur In The Pamidronate‐Treated Animals (P< 0.05). The Cv Of Paired Measurements Of Bmd Was 2.7% At The Spine And 1.5% Of A Femur, Respectively. The Bmc Of The Lumbar Spine And Femur Was Closely Correlated With The Ashed Weight Of The Same Bones (R= 0.92 And 0.85, Respectively).

Intermittent administration of PTH type 1 receptor (PTH1R) agonists increases bone remodeling, with greater stimulation of bone formation relative to bone resorption causing net gains in bone mass. This pharmacodynamic feature underlies the bone-building effects of teriparatide and abaloparatide, the only PTH1R agonists approved to reduce osteoporotic fracture risk in postmenopausal women. This study in 8-week-old female mice compared bone resorption and formation responses to these agents delivered at the same 10 μg/kg dose, and a 40 μg/kg abaloparatide dose was also included to reflect its 4-fold higher approved clinical dose. Peptides or vehicle were administered by daily supra-calvarial subcutaneous injection for 12 days, and local (calvarial) and systemic (L5 vertebral and tibial) responses were evaluated by histomorphometry. Terminal bone histomorphometry data indicated that calvarial resorption cavities were similar in both abaloparatide groups versus vehicle controls, whereas the teriparatide group had more calvarial resorption cavities compared with the vehicle or abaloparatide 40 μg/kg groups. The bone resorption marker serum CTX was significantly lower in the abaloparatide 40 μg/kg group and similar in the other two active treatment groups compared with vehicle controls. Both peptides increased trabecular bone formation rate (BFR) in L5 and proximal tibia versus vehicle, and L5 BFR was higher with abaloparatide 40 μg/kg versus teriparatide. At the tibial diaphysis, periosteal BFR was higher with abaloparatide 40 μg/kg versus vehicle or teriparatide, and endocortical BFR was higher with teriparatide but not with abaloparatide 10 or 40 μg/kg versus vehicle. Few differences in structural or microarchitectural bone parameters were observed with this brief duration of treatment. In summary, calvarial bone resorption cavity counts were higher in the teriparatide group versus the vehicle and abaloparatide 40 μg/kg groups, and the abaloparatide 40 μg/kg group had lower serum CTX versus vehicle. L5 and tibial trabecular bone formation indices were higher in all three active treatment groups versus vehicle. The abaloparatide 40 μg/kg group had higher L5 trabecular BFR and tibial periosteal BFR versus teriparatide, whereas tibial endocortical BFR was higher with teriparatide but not abaloparatide. Together, these findings in female mice indicate that an improved balance of bone formation versus bone resorption is established shortly after initiating treatment with abaloparatide.

•A significantly greater proportion of abaloparatide/alendronate patients had BMD increases over 0, 3 and 6 percent versus placebo/alendronate.•BMD responses were higher at all anatomic sites and for all thresholds assessed for abaloparatide/alendronate versus placebo/alendronate•This study provides further evidence of cumulative benefit from sequential treatment with an anabolic agent followed by an antiresorptive.

Raloxifene is a selective estrogen receptor modulator that has been shown to prevent bone loss in postmenopausal women. Whether it also reduces the risk of fracture remains uncertain, prompting the present trial, the Multiple Outcomes of Raloxifene Evaluation (MORE) study. The randomized, blinded, placebo-controlled trial enlisted 7705 women in 25 countries, ranging in age from 31 to 80 years, who had been postmenopausal for 2 years or longer and met World Health Organization criteria for osteoporosis. Participants were assigned to receive raloxifene in a daily dose of 60 or 120 mg or placebo pills, and, in addition, all of them were given supplemental calcium and cholecalciferol. Follow-up extended for at least 3 years. Baseline and follow-up radiographs were available for 89 percent of women entering the study.